The mode of administration of a drug can affect its bioavailability and pharmacokinetic profile, as well as patient compliance. Patient compliance is best when the mode of administration is convenient and does not involve patient discomfort. Oral administration is often the preferred mode.
Despite the advantages of oral administration, it is still unworkable for many drugs. One problem with oral administration arises because there can be extensive metabolism of a drug during transit from the gastrointestinal tract to the general circulation. For example, the intestinal mucosa, through which an orally administered drug passes before it enters the circulatory system, is enzymatica))y very active and can thus metabolize a drug in many ways. Therefore, bioavailability of orally administered drugs can be very low.
With the advent of recombinant DNA technology, many more peptides are available for pharmaceutical use than ever before. However, oral administration of peptides is particularly problematic because peptide bonds are cleaved by proteases secreted into the gut, as part of the digestive process. The only broadly applicable means of administration of peptides at this time is parenteral administration. This is not always a practical or desirable route, especially if the drug is required to be administered chronically, such as in the case of insulin treatment for diabetes. Many individuals are reluctant or unable to self-inject a parenterally-formulated drug on a routine basis.
Some of the shortcomings of oral and parenteral administration can be circumvented by administering the drug by a route which avoids digestive and gut-wall metabolism, and also eliminates the need for injection. Examples of such alternative routes include transdermal (Rajadgyaksha, V. et al., PCT publication WO 88/04938), nasal (Carey, M. C., et al., U.S. Pat. No. 4,746,508), and pulmonary delivery.
Transdermal administration is not workable for many drugs which cannot penetrate the dermis unless they are formulated with permeation enhancers, such as DMSO, which can cause undesirable side effects. Nasal administration using low-toxicity permeation enhancers of the fusidic acid derivative family has been effective in many instances (Carey, M. C., supra), however, the surface area of nose is relatively small.
Pulmonary delivery offers several potential advantages, particularly in the case of administration of drugs intended to treat conditions affecting the lungs themselves, because some drugs have difficulty reaching the lungs by any route of administration. For instance, Pseudomonas infections in patients with cystic fibrosis can be difficult or impossible to treat, since antibiotics delivered by conventional modes of administration do not easily reach the lungs and therefore cannot stop the spread of infection.
Currently, pulmonary drug delivery methods include mechanical means such as aerosols and inhalers, which have been employed with or without the addition of liposomes to the drug formulation. These methods are effective at getting the drug to the lung, however, they do not ensure efficient transport across the pulmonary surface.
Hayward, J. A. (PCT patent publication #WO 87/01586) discloses using liposomes which contain a drug or diagnostic agent in an aerosol composition for inhalation. Although the liposome-containing drug is more effective than the drug in solution, the drug is still not efficiently administered.
A number of studies have been done which involved the pulmonary administration of lipids for the treatment of respiratory distress. Most of these studies administer liposomes only, without addition of pharmaceutically active substances (Yoshida, T., et al., U.S. Pat. No. 4,571,334). A few groups have investigated the administration of peptides with liposomes for the treatment of respiratory distress (Schilling, et al., U.S. Pat. No. 4,659,805 and Whitsett, J. A., PCT patent publication WO 87/01586). In these cases, however, the lipids were not used as a drug delivery vehicle. Rather the lipid/protein complex was administered to compensate for a deficiency of a normally present lipid/protein complex, which reduces surface tension along the alveolar surfaces.
The compositions and methods of the present invention are widely applicable to a variety of pharmaceutically active substances which for the first time can be efficiently delivered across pulmonary surfaces.